Along with other factors, free radicals and inefficient antioxidant defense system have been implicated in the pathogenesis of rheumatoid arthritis and other inflammatory diseases. Fish oil (FO, containing omega-3 fatty acids) dramatically extends the life span and delays the onset and progression of autoimmunity in autoimmune-prone mice compared to corn oil (CO; containing in omega-6 lipids). Our recent observations have indicated that FO prolongs the life of autoimmune mice through enhancing the activities and expression of antioxidant enzymes and decreasing lipid peroxidation. As long chain fatty acids are generally more susceptible to lipid peroxidation, the protective effect exerted by omega-3 lipids may perhaps be related to the level of vitamin E (vit-E) in the diet. The principal hypothesis is that though dietary omega-3 lipids increase the level of long chain polyunsaturated fatty acids in subcellular membranes, and vit-E in adequate level, can enhance antioxidant defense system, thereby may protect subcellular membranes from damage by free radicals, and delay the progression of autoimmune disease in these mice. To test whether the protective effect of FO is related to the level of vit-E in the diet, the following specific aims will be carried out: (1) The influence of 10% CO and 10% FO (at low and high levels of vit-E) on survival, progression of lupus disease in MRL/lpr mice, serum Vit-E, anti-cardiolipin, anti-DNA antibody levels, will be determined. (2) To determine whether the immunomodulatory effect of omega-6 and omega-3 lipids is linked to the vit-E level in the diet, cross-sectional studies (3m and 6m) in MRL/lpr, MRL/+/+ and C57BL/6 mice carried out (10% CO or FO diets with low and high levels of vit-E) to analyze: proliferative response, lymphoid cell subsets, cytokine production by spleen cells (IL-2, IL-4 , IL-6, PGE2), mRNA expression and protein levels of Fas; c-myc, c-ras oncogenes, and transforming growth factor (TGFbeta3) by spleen cells. (3) To elucidate whether the protective effect on antioxidant defense system by omega-3 lipids is related to level of vit-E in the diets, the activities and mRNA expression of antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase), Vit-E levels, fatty acid composition, lipid peroxidation will be determined in the tissues saved from the cross- sectional studies. As omega-3 dietary lipids, when supplemented with adequate vit-E, have a tremendous potential in delaying murine lupus, the data collected from this proposal will enable us to plan adequately antioxidant supplemented lipid therapy to enhance the efficacy of drugs as well as reduce their toxicity. Some of these lipids when taken prophylactically early enough can lower the incidence of lupus, especially in people who are genetically susceptible to develop autoimmune disease.